This was originally a guest post on The Trenches of Discovery. Thanks, Shaun!
One out of every 8,000 humans is born with some of their internal organs on the wrong side of their body, a condition which can have serious medical consequences. Although we’re usually described as symmetric, that’s only superficially true. Like other vertebrates, we look symmetric from the outside but our internal organs show left-right asymmetry; unless you happen to be a Time Lord, you have only one heart which is normally located on the left side of your chest. Changes to the organization of the internal organs can lead to cardiac defects, misalignment of the bowel and other serious problems. Many genes are known to play a role in establishing this asymmetry, but we still don’t fully understand its evolutionary and developmental origins. Earlier this year, a paper published in the journal PNAS described how this asymmetry is established by subcellular components early in embryonic development.
Experiments with plants have already shown that subcellular structures can have an effect on macroscopic organs. Cells are highly organized, dynamic, complex living things, more kin to a vast city than to a sack of fluid. The cytoskeleton is an important part of this structure and plays a critical role in many processes, including determining the shape of the cell and acting as a transportation network, much like a road and rail network in a city. The cytoskeleton is a network of different kinds of filaments and microtubules, the roads and rails themselves, which in turn are built out of the proteins actin and tubulin. A decade ago, scientists discovered that a mutation in one of these building blocks, tubulin, could have far-reaching effects in plants. The mutated tubulin changes the shape of the cytoskeleton, twisting it; this changes the shape of the cells, which leads to flowers and other organs being twisted in turn.
Tubulins are a basic component of the machinery of life, found in every kind of cell. Based on the belief that left-right asymmetry is a consequence of subcellular structures, a team of scientists led by Michael Levin at Tufts University in Massachusetts decided to investigate the role of tubulin in establishing this asymmetry. They injected embryos of the frog Xenopus laevis with mutated forms of two tubulin related genes, Tubgcp2 and Tuba4, and followed the developing embryos to find out how frequently the internal organs were located on the wrong side of the body, a condition known as heterotaxia. About one quarter of the injected embryos were heterotactic, with half of those showing abnormalities in at least two organs. Amazingly, this was only true if the embryos were injected when they were still only a single cell; embryos that had already divided into two or four cells weren’t affected by the mutated tubulin. Whatever the mechanism involved may be, tubulin is clearly critical to a very early decision in the embryo which has long term effects on the positioning of internal organs.
The researchers weren’t content to simply show that tubulin has a role in establishing internal asymmetry; they also wanted to explore how it might be accomplishing this. One possibility is that changes to tubulin alter the structure of the microtubules which affects transport within the cell. The cytoskeleton is known to be biased towards the right half of the frog embryo, leading certain molecular motors and their cargo to be preferentially transported to that side. This rightwards bias disappeared in the mutant embryos, supporting the idea that the mutated tubulin somehow disrupts the regular pattern of transport. The researchers also used the mutant embryos as a tool to fish out a whole suite of maternal factors that depend on tubulin in order to be localized to one side of the embryo, including cytoskeletal and transport-related proteins which can form the basis of future research into how this asymmetry is maintained and propagated.
Finally, the team co-operated with scientists at the University of Illinois and Cincinnati Children’s Hospital Research Foundation to verify that the same process takes place in other organisms. They found that introducing mutations in tubulin led to changes in left-right asymmetry in both human cell cultures and the nematode Caenorhabditis elegans. Since tubulin seems to play a similar role in establishing asymmetry in frogs, nematodes and humans, the authors are confident in asserting that this is an ancient and conserved mechanism of left-right patterning.
In addition to its implications for an important class of human birth defects, this is a thrilling developmental story. It’s quite amazing to see how changes in subcellular components can propagate up through cells, tissues and organs to have an effect on the overall layout of the organism itself. While the authors describe this as a mechanism which has been conserved during evolution, I think it may also be a common physical principle which different groups have taken advantage of. Whatever its evolutionary origins, it’s a mechanism which I find profoundly beautiful. The idea that the orientation of the cytoskeleton is amplified by changes in subcellular transport to have major developmental and physiological consequences is so elegant that I can’t help but revel in it. This is the kind of story that makes me fall in love with science all over again. The world may be fabulously rich and complex, but sometimes the explanation can be sublime in its simplicity.
Lobikin, M., Wang, G., Xu, J., Hsieh, Y., Chuang, C., Lemire, J., & Levin, M. (2012). Early, nonciliary role for microtubule proteins in left-right patterning is conserved across kingdoms Proceedings of the National Academy of Sciences, 109 (31), 12586-12591 DOI: 10.1073/pnas.1202659109